Syntheses, crystal structures and Hirshfeld surface analysis of three salts of 1-(4-nitrophenyl)piperazine

Three salts of 4-nitrophenylpiperazine were synthesized and their crystal structures determined via X-ray diffraction.

The structures and Hirshfeld surface analysis of three salts of 1-(4-nitrophenyl)piperazine are discussed. In 4-(4-nitrophenyl)piperazin-1-ium salicylate (C 10 H 14 N 3 O 2 + ÁC 7 H 5 O 3 À ), there are strong hydrogen bonds between cation and anion and the 4-nitrophenyl substituent occupies an equatorial position in the piperazinium ring. The cation and anion are linked together by supramolecular interactions [graph-set notation of hydrogen bonding C 2 2 (6) propagating in the a-axis direction]. Additionally, there isstacking involving the salicylate anion and the piperazinium cation in adjacent asymmetric units as well as a C-HÁ Á Á interaction between a hydrogen atom on the piperazine ring and the phenyl ring within the salicyclate anion. In bis[4-(4-nitrophenyl)piperazin-1-ium] bis(4-fluorobenzoate) trihydrate (2C 10 H 14 N 3 O 2 + Á2C 7 H 4 FO 2 À Á3H 2 O), there are two cations, two anions, and three water molecules of solvation in the asymmetric unit, all linked by hydrogen bonds [graph-set notation of hydrogen bonding R 2 2 (20) between adjacent cations and R 3 3 (9) between a cation and its adjacent anion]. In the anion, the 4-nitrophenyl ring occupies an axial substitution position in the piperazinium ring, which is relatively rare. Within the asymmetric unit, the phenyl groups in the cations show an offsetinteraction. Additionally, there is a C-HÁ Á Á interaction between a hydrogen atom on the phenyl ring within a cation and the phenyl ring within an anion. In 4-(4-nitrophenyl)piperazin-1-ium 3,5-dinitrobenzoate (C 10 H 14 N 3 O 2 + ÁC 7 H 4 N 2 O 6 À ), there is a strong N-HÁ Á ÁO hydrogen bond linking the cation and anion and the 4-nitrophenyl ring occupies an axial substitution position in the piperazinium ring, as seen in the previous structure. In the crystal, the cation and the anion form a complex threedimensional hydrogen-bonded array involving R 2 2 (8), R 4 4 (12) and R 4 4 (20) rings propogating in the a-axis direction. The nitrophenyl group is disordered with occupancies of 0.806 (10) and 0.194 (10).

Chemical context
Piperazines and substituted piperazines are important pharmacophores that can be found in many biologically active compounds across a number of different therapeutic areas (Berkheij, 2005), being used as antifungal (Upadhayaya et al., 2004), anti-bacterial, anti-malarial and anti-psychotic agents (Chaudhary et al., 2006). An insight into advances on the antimicrobial activity of piperazine derivatives has been reported (Kharb et al., 2012).
Piperazines are among the most important building blocks in today's drug discovery and are found in biologically active compounds across a number of different therapeutic areas (Brockunier et al., 2004;Bogatcheva et al., 2006). A review of pharmacological and toxicological information for piperazine derivatives is given by Elliott (2011). 4-Nitrophenylpiperazinium chloride monohydrate has been used as an intermediate in the synthesis of anticancer drugs, transcriptase inhibitors and antifungal reagents and is also an important reagent for potassium channel openers, which show considerable biomolecular current-voltage rectification characteristics (Lu, 2007).
The inclusion behaviour of 4-sulfonatocalix[n]arenes (SCXn) (n = 4, 6, 8) with 1-(4-nitrophenyl)piperazine (NPP) has been investigated by UV spectroscopy and fluorescence spectroscopy at different pH values (Zhang et al., 2014). The design, synthesis and biological profiling of aryl piperazinebased scaffolds for the management of androgen-sensitive prostatic disorders has been published (Gupta et al., 2016). 4-Nitrophenylpiperazine was the starting material in the synthesis and biological evaluation of novel piperazinecontaining hydrazone derivatives (Kaya et al., 2016). Several previous investigations in this area are outlined in the Database Survey section.

Figure 2
Diagram showing atom labelling indicating four rings A-D, the arrangement of cation and anion and the three water molecules of solvation in 2. In the conformation of rings A-D, the dihedral angles between the 4nitrophenyl rings in rings B and C, the 4-nitrophenyl ring and nitro group in ring B, the 4-nitrophenyl ring and nitro group in ring C, the piperazine ring and the 4-nitrophenyl ring in ring B, the piperazine ring and 4-nitrophenyl ring in ring C, the fluorobenzene ring in ring D and the phenyl ring in ring C, and the fluorobenzene ring in A and the phenyl ring in C are 11.4 (4), 1.1 (2), 0.2 (2), 141.72 (16), 145.17 (17), 101.47 (17) and 103.32 (17) , respectively. The third and fourth angles listed indicate that the 4-nitrophenyl ring occupies an axial position in both cations, which is relatively rare. In a previous paper containing eleven analogous structures, only one had this substitution pattern (Archana et al., 2022). Compound 3, (4-nitrophenylpiperazinium 3,5-dinitrobenzoate; C 10 H 14 N 3 O 2 ÁC 7 H 4 N 2 O 6 ), crystallizes in the monoclinic space group C2/c with eight formula units in the unit cell. The structure consists of a 4-nitrophenylpiperazinium cation and a 3,5-dinitrobenzoate anion linked by a strong N-HÁ Á ÁO hydrogen bond [HÁ Á ÁO = 1.77 (2) Å ; NÁ Á ÁO = 2.705 (3) Å ; N-HÁ Á ÁO = 170.7 (17) , Table 3] as shown in Fig. 3. The nitrophenyl ring is disordered with occupancies of 0.806 (10)/ 0.194 (10). In the cation, the dihedral angles between the piperazine ring and the major component of the 4-nitrophenyl ring, and the phenyl ring and its attached nitro group are 62.4 (1) and 10.1 (7) , respectively. The former angle is indicative of the fact that the 4-nitrophenyl ring occupies an axial position, as it also did in 2. In the anion, the dihedral angle between the 3,5-dinitrobenzoate phenyl ring and its carboxylate substituent is 18.7 (1) .

Figure 3
Diagram showing atom labelling and the arrangement of cation and anion in 3 (only major component shown). Hydrogen bonds are shown by dashed lines. Atomic displacement parameters are at the 30% probability level.

Figure 4
Packing diagram for 1 showing the zigzag chain of hydrogen bonds [graph-set notation C 2 2 (6)] propagating in the a-axis direction.
For 2, there are two anions and two cations as well as three water molecules of solvation in the asymmetric unit. This leads to a complex three-dimensional array of hydrogen bonding involving both R 2 2 (20) motifs between rings B and C, and R 3 3 (9) motifs between rings C and D as well as one water molecule, as seen in Fig. 6. There are also C-HÁ Á ÁF interactions between adjacent fluorobenzoate anions linking them into centrosymmetric dimers (symmetry code: 3 2 + x, 1 2 À y, À 1 2 + z; see Table 2 376   Packing diagram for 2 showing the complex three-dimensional array of hydrogen bonding involving both R 2 2 (20) motifs between rings B and C (middle left in diagram with ring B on right and ring C on left) and R 3 3 (9) motifs between rings C and D (ring D on upper left of diagram) as well as one water molecule.    for numerical details). These interactions are shown clearly as spikes in the fingerprint plots delineated into C-HÁ Á ÁF and N-HÁ Á ÁO interactions (Figs. 7 and 8, respectively). In the crystal, the phenyl ring in B forms an offsetinteraction with the phenyl ring in C [Cg2Á Á ÁCg4 distance, 3.8568 (7) Å ; slippage of 1.835 Å ; perpendicular distance of 3.454 (2) Å ; Cg2 and Cg4 are the centroids of the C1B-C6B and C1C-C6C rings, respectively]. Additionally, there is a C-HÁ Á Á interaction between a hydrogen atom on the phenyl ring in C and the phenyl ring in D [H6CÁ Á ÁCg6 i , 2.91; C6-H6CÁ Á ÁCg6 i angle of 161 , symmetry code: (i) 1 À x, 1 À y, Àz; Cg6 is the centroid of the C11D-C16D ring].

Refinement
Crystal data, data collection and structure refinement details for the three structures are summarized in Table 4. In all structures, a riding model was used for the H atoms attached to C with U iso (H) = 1.2U eq (C) while the N-H and water O-H hydrogen atoms were refined isotropically. In 3 the nitrophenyl group is disordered with occupancies of 0.806 (10)/ 0.194 (10) and constrained to have similar metrical parameters.
research communications Figure 11 Reaction scheme for the synthesis of 1, 2 and 3. SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015b); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).  Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Bis[4-(4-nitrophenyl)piperazin-1-ium] bis(4-fluorobenzoate) trihydrate (2)
Crystal data where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.19 e Å −3 Δρ min = −0.18 e Å −3 Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.